Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current methods of treating cancer patients with chemotherapeutics do not account for interpatient variability in the expression of particular target genes. This variability leads to unpredictable tumor responses and host toxicity. The approach we have taken is to determine gene expression levels in the metabolic pathways of drugs used in the treatment of gastrointestinal tumors. One of the main obstacles in the evaluation and determination of these markers has been the limitations of available technology. Many advances have been made in the development of more sophisticated techniques and the ability to perform these techniques on paraffin-embedded tumor tissue. In fact, with the identification of genetic polymorphisms, these markers may be obtained from peripheral blood specimens, thus making access to tissues a moot issue. An immediate goal is the application of this nascent technology and incorporation of these data in prospective clinical trials that would stratify patients according to their molecular profile. The ability to predict with a high degree of accuracy which patients are likely to respond to treatment and identify those who are not likely to respond will significantly influence the design of new treatment regimens with fluoropyrimidines and platinum. Tumors with high TS, TP, and DPD expression levels should be treated with such non-TS-directed anticancer drugs as irinotecan or oxaliplatin, or in combination with 5-FU. Patients with high expression of ERCC1 should be treated with nonplatinum-based regimens, whereas patients with low levels would be good candidates for cisplatin or oxaliplatin. We now understand that molecular determinants play an important role in response to 5-FU. With the development of new effective anticancer drugs such as irinotecan and oxaliplatin, it is important to gain a better understanding about the metabolism of these new active agents and mechanisms of resistance. It is essential to understand why some patients develop life-threatening toxicity and why some tumors are resistant to irinotecan or oxaliplatin. With the integration of novel-targeted therapies such as Erbitux and Avastin, molecular characterization and profiling will become more important for patient selection. Preliminary data suggest that germ line polymorphisms of cyclin D and gene expression levels of VEGF are associated with efficacy of Erbitux therapy.
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PMID:Pharmacogenomics and colorectal cancer. 1716 68

Adjuvant therapy for colorectal cancer consists primarily of combinations of 5-fluorouracil/leucovorin (5-FU/LV) (with infusional or bolus 5-FU) with oxaliplatin or oral capecitabine. The angiogenesis inhibitor bevacizumab and the epidermal growth factor receptor inhibitor cetuximab have shown activity when combined with 5-FU/LV-based regimens as first-line treatment of advanced disease and are currently being evaluated as part of adjuvant therapy in colon cancer. Bevacizumab is being evaluated in combination with FOLFOX4 (5-FU/LV/oxaliplatin), FOLFOX6, or XELOX (capecitabine/oxaliplatin) in the National Surgical Adjuvant Breast and Bowel Project C08 trial, the AVANT (AVastin adjuvANT) trial, and the Intergroup Rectal Adjuvant trial. Cetuximab is being evaluated in combination with FOLFOX4 and FOLFOX6 in the North Central Cancer Treatment Group (NCCTG) N0147 trial and the Pan European Trials in Adjuvant Colon Cancer (PETTAC) 8 trial.
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PMID:Targeted agents for adjuvant therapy of colon cancer. 1717 86

Vascular endothelial growth factor (VEGF) is a key mediator in the pathogenesis of renal cell carcinoma (RCC). VEGF is up-regulated in clear cell RCC as a result of loss of the von Hippel-Lindau tumor suppressor gene and subsequent activation of the hypoxia response pathway. VEGF expression drives the migration and proliferation of endothelial cells to support the extensive angiogenesis in RCC. Strategies have been developed to bind and neutralize VEGF and have been investigated in RCC with promising results. Bevacizumab, a VEGF ligand-binding antibody, has shown prolonged time-to-progression versus placebo in treatment-refractory RCC patients and is being investigated currently in multiple RCC settings. VEGF-Trap is also a VEGF binding molecule with ongoing investigation in RCC.
Clin Cancer Res 2007 Jan 15
PMID:Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma. 1725 3

The treatment of advanced renal cell carcinoma (RCC) has undergone a major change with the development of potent angiogenesis inhibitors and targeted agents. Several multitargeted tyrosine kinase inhibitors, sorafenib and sunitinib, have already been approved for the treatment of advanced RCC. Temsirolimus (CCI-779), a mammalian target of rapamycin inhibitor, has shown a survival advantage over IFN in advanced, poor-prognosis RCC patients. Bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF) A, has also shown promising clinical activity. Benefits attributable to these agents have been recognized by high objective response rates (sunitinib), significant increases in progression-free survival (sunitinib, sorafenib and bevacizumab), or improved overall survival (temsirolimus). These agents mediate much of their effect through inhibition of the hypoxia-inducible factor (HIF)-VEGF-VEGF receptor axis. Their inhibitory activity for the signaling of platelet-derived growth factor (PDGF) receptor beta or kinases like c-Raf may contribute to the antitumor effects of the multitargeted kinase inhibitors. Nevertheless, all four single agents rarely, if ever, induce complete responses and, at present, all patients develop resistance and, ultimately, progress during therapy. A critical need exists to develop strategies that may increase the degree of the antitumor effects with the hope of inducing more complete responses impeding the onset of or elimination of refractory disease. Combinations of these and other targeted agents may overcome the resistance that develops with single-agent therapy and could be incorporated either as part of initial therapy or later when disease resistance develops. Approaches aimed at combining these agents can be based on the genetics and biology of clear cell RCC. von Hippel-Lindau loss leads to an increase in cellular levels of HIF (HIF-1alpha or HIF-2alpha) leading to increased expression of a number of hypoxia-regulated genes critical to cancer progression. Combinations of targeted agents may block several of these mediators (VEGF, epidermal growth factor receptor, and PDGF), so-called horizontal blockade. Blockade could also take place at two levels of the pathways (vertical blockade), either at HIF and VEGF or at VEGF and VEGF receptor signaling. Many of the above strategies are ongoing and will require careful phase 1 determination of toxicity and even more rigorous phase 2 analysis before moving onto phase 3 trials.
Clin Cancer Res 2007 Jan 15
PMID:Opportunities and obstacles to combination targeted therapy in renal cell cancer. 1725 7

The purpose of this study was to assess the response rate and toxicity of paclitaxel, carboplatin, and bevacizumab (PCB) primary induction therapy for the treatment of advanced-stage ovarian carcinoma. Twenty patients were treated with paclitaxel (175 mg/m(2)), carboplatin (AUC of 5 IV), and bevacizumab (15 mg/kg) of body weight; q21 days for six cycles. Bevacizumab was administered at cycles two through six. Patients received 116 cycles of PCB chemotherapy (median = 6, range 2-6) and were evaluable for toxicity assessment. Grade 3 and 4 neutropenia developed in 23.3% and 25% of cycles, with no incidence of grades 3/4 thrombocytopenia or anemia. Prior to cycle six, one patient was removed from the study due to grade 3 neuropathy and another patient was excluded due to clinical deterioration. There was no incidence of gastrointestinal perforations, and only two patients demonstrated grade 3 hypertension (HTN). No grade 4 HTN was observed. Eighteen patients were evaluated for response following induction therapy. Six demonstrated a complete response (30%) and ten exhibited a partial response (50%), resulting in a total response rate of 80%. One patient exhibited stable disease (5%), and one demonstrated disease progression (5%). The lack of bowel perforations and wound complications should mitigate some concerns regarding these side effects. This study suggests that first-line treatment with PCB can be safely administered to previously untreated advanced-stage ovarian carcinoma patients. The favorable toxicity results and reasonable response rate warrant additional study in a larger patient population.
Int J Gynecol Cancer
PMID:A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer. 1734 5

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in United States. For nearly 50 years, fluorouracil has been the only anticancer drug proven to benefit patients with metastatic CRC (mCRC), and it continues to be the backbone on which most treatment regimens are built. In the past 10 years, development of the topoisomerase I inhibitor irinotecan (Camptosar), the third-generation platinum analog oxaliplatin (Eloxatin), and the oral fluoropyrimidine capecitabine (Xeloda) advanced mCRC treatment and opened up an era of combination chemotherapy. More recently, monoclonal antibodies such as bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix) have become available for use in mCRC treatment in combination with cytotoxic agents and as monotherapies. The addition of these targeted agents to the mCRC treatment armamentarium has resulted in more therapeutic options and improved treatment outcomes for the patients. The prospect of mCRC treatment is ever promising as more targeted agents such as vatalanib are being introduced and as intelligent combination regimens are being designed based upon a better understanding of pharmacokinetics. In this article we review various treatment options, including cytotoxic and targeted agents, currently available for patients with mCRC.
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PMID:Treatment of metastatic colorectal cancer: from cytotoxic agents to molecular agents and multitargeted strategies. 1735 13

Bevacizumab is the first anti-angiogenic agent inhibiting vascular endothelial growth factor (VEGF) for treatment of patients suffering from cancer. Life-threatening hemoptysis is the most serious adverse effect of bevacizumab. The inhibition of VEGF is a possible mechanism involved in the destruction of normal lung tissue and subsequent hemoptysis. We report a case of bevacizumab-related hemoptysis and associated bronchoscopic findings that were successfully treated with rigid bronchoscopy and laser photocoagulation.
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PMID:Bronchoscopy for bevacizumab-related hemoptysis. 1736 26

As targeted therapies for cancer become increasingly integrated into standard practice, appropriate selection of the patients most likely to benefit from these therapies is now receiving critical scrutiny. Early experience with therapies directed at targets that are definitively overactive (e.g. the bcr-abl tyrosine kinase targeted by imatinib) or over-expressed [e.g. the human epidermal growth factor receptor 2 (HER2) targeted by trastuzumab] has generated the perception that pre-treatment target assessment is a pre-requisite for therapy with all targeted agents. However, emerging evidence suggests that this is not presently feasible for anti-angiogenic agents. Despite considerable evidence for the association of intratumoral and/or plasma vascular endothelial growth factor (VEGF) levels with tumor progression and/or poor prognosis, pre-treatment VEGF levels do not appear to be predictive of response to anti-angiogenic therapy. This may possibly be due to the complexity of the angiogenic pathways and the limitations associated with current methods of VEGF detection and quantification; e.g. low assay sensitivity and lack of standardized methods could prevent detection of very small increases in VEGF, which may be clinically important in patients with tumors that are highly dependent on this growth factor. In addition to a general lack of agreement as to the relative clinical relevance of circulating versus tumor VEGF levels, the absence of a 'gold standard' VEGF detection assay and the lack of a predefined, clinically relevant cut-off pose a significant hindrance to the clinical utility of VEGF measurements for therapy selection. Given the fundamental importance of angiogenesis for tumor growth and progression, and the key role of VEGF in these processes, presently it seems appropriate to view anti-VEGF agents such as bevacizumab (Avastin) as having potential utility, independently of pre-treatment screening. Further research is needed to define the relationship between potential surrogate markers of VEGF pathway activity and clinical outcomes.
Cancer Chemother Pharmacol 2007 Jul
PMID:Challenges for patient selection with VEGF inhibitors. 1737 72

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.
Clin Cancer Res 2007 Apr 01
PMID:The potential of antiangiogenic therapy in non-small cell lung cancer. 1740 76

Angiogenesis is defined as the formation of new blood vessels from a pre-existing vascular bed. By supplying nutrients and oxygen and removing waste products in malignant tumors, it is an essential process that regulates cancer growth and dissemination. This process is regulated by both pro- and antiangiogenic compounds. Vascular endothelial growth factor is one of the most important and best-studied proangiogenic factors. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to inhibit angiogenesis and is proving to be of clinical benefit in a variety of tumor types. The strongest evidence comes from studies in advanced colorectal and non-small-cell lung cancer, with growing evidence in breast and epithelial ovarian tumors. The duration and timing of bevacizumab's use is currently the focus of several ongoing clinical trials.
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PMID:Bevacizumab in the management of solid tumors. 1742 64


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